What are the potential non-cardiac and non-pulmonary causes of shortness of breath in a patient, and how should they be evaluated and managed?

Non-Cardiac and Non-Pulmonary Causes of Shortness of Breath

After excluding cardiac and pulmonary etiologies through appropriate testing (BNP, chest X-ray, spirometry, echocardiography), the remaining non-cardiac and non-pulmonary causes of dyspnea include renal disease, hepatic disease, hematologic disorders, metabolic derangements, neuromuscular conditions, gastrointestinal pathology, deconditioning, psychiatric disorders, and obesity-related hypoventilation. 1, 2

Systematic Approach to Non-Cardiac/Non-Pulmonary Dyspnea

Initial Exclusion of Cardiac and Pulmonary Causes

Before attributing dyspnea to non-cardiopulmonary causes, you must definitively rule out the most common etiologies:

• Obtain BNP or NT-proBNP to exclude heart failure (BNP <100 pg/mL has 94% negative predictive value for cardiac causes) 3, 4
• Perform chest X-ray to identify infiltrates, effusions, cardiomegaly, or hyperinflation 1, 3
• Complete spirometry to exclude obstructive or restrictive lung disease before prescribing any inhalers 3, 5
• Order echocardiography if BNP is elevated or cardiac dysfunction is suspected 3, 4

Major Non-Cardiac/Non-Pulmonary Causes

Renal Disease

• Kidney failure or nephrotic syndrome can cause dyspnea through fluid overload and peripheral edema mimicking heart failure 1
• Obtain urinalysis to assess for proteinuria and basic metabolic panel to evaluate renal function 1, 2
• Recognize that kidney venous congestion can worsen renal function independent of cardiac output 6

Hepatic Disease

• Liver failure or cirrhosis presents with ascites and peripheral edema that can mimic cardiac congestion 1
• Perform abdominal ultrasound to assess for cirrhosis and portal hypertension 1

Hematologic Disorders

• Anemia reduces oxygen-carrying capacity and causes exertional dyspnea 1, 2
• Obtain complete blood count as part of initial evaluation 2

Severe Obesity

• Obesity with peripheral edema can cause dyspnea through multiple mechanisms including restrictive chest wall mechanics and obesity hypoventilation syndrome 1
• Calculate BMI and consider obesity as a primary cause when BMI >30 kg/m² 1
• Recognize that obesity can paradoxically lower BNP levels, potentially masking cardiac dysfunction 6

Neuromuscular Diseases

• Neuromuscular inflammation and injuries affecting respiratory muscles can cause dyspnea 1
• Evaluate with pulmonary function tests showing restrictive pattern with reduced maximal inspiratory/expiratory pressures 1, 2
• Consider referral to neurology for specialized testing if neuromuscular disease is suspected 1

Gastrointestinal Pathology

• Gastroesophageal reflux disease (GERD) can cause dyspnea through aspiration or vagal reflexes 7
• Foreign body aspiration (as demonstrated in a case of bean aspiration causing obstructive symptoms) should be considered when symptoms fail to respond to standard therapy 7

Deconditioning

• Cardiovascular deconditioning contributes significantly to chronic exertional dyspnea in patients with reduced functional capacity 1
• The American Thoracic Society recommends pulmonary rehabilitation and exercise training for patients with long-standing dyspnea and reduced functional capacity 1
• Recognize that deconditioning after prolonged bed rest can cause orthostatic hypotension and dyspnea 1

Psychiatric Disorders

• Psychogenic disorders account for a portion of chronic dyspnea cases, particularly when organic causes are excluded 2
• Consider psychological evaluation when history suggests psychiatric disorder and all organic testing is negative 1
• Distinguish from exercise-induced hyperventilation which can masquerade as asthma 1

Metabolic and Systemic Conditions

• Metabolic acidosis from various causes (diabetic ketoacidosis, uremia, lactic acidosis) stimulates respiratory drive 1
• Thyroid disorders (both hyperthyroidism and hypothyroidism) can cause dyspnea 2
• Systemic infections can adversely affect activity tolerance and cause dyspnea 1

Diagnostic Algorithm for Non-Cardiopulmonary Dyspnea

Step 1: Confirm cardiac and pulmonary causes are excluded

• BNP <100 pg/mL rules out heart failure 3
• Normal chest X-ray excludes major pulmonary pathology 3
• Normal spirometry excludes obstructive/restrictive lung disease 3

Step 2: Obtain targeted laboratory testing

• Complete blood count (anemia) 2
• Basic metabolic panel (renal function, electrolytes, glucose) 2
• Urinalysis (proteinuria, nephrotic syndrome) 1
• Thyroid function tests 2
• Arterial blood gas if SpO2 <92% (metabolic acidosis, hypercapnia) 3

Step 3: Consider imaging based on clinical suspicion

• Abdominal ultrasound for suspected cirrhosis 1
• CT chest if foreign body aspiration suspected and symptoms fail standard therapy 7

Step 4: Specialized testing when indicated

• Pulmonary function tests with maximal inspiratory/expiratory pressures for neuromuscular disease 1
• Bronchoscopy if foreign body or unusual airway pathology suspected 7
• Psychological evaluation if all organic causes excluded 1

Critical Pitfalls to Avoid

• Never prescribe inhalers without spirometry confirmation of obstructive airway disease—one study found 28.4% of patients on inhalers had no evidence of lung disease 5
• Do not assume obesity is protective—while obesity lowers BNP levels, it independently causes dyspnea through multiple mechanisms 1, 6
• Recognize multifactorial etiology—more than 30% of chronic dyspnea cases have multiple contributing causes 1
• Do not dismiss persistent symptoms—if dyspnea fails to respond to standard therapy, consider uncommon causes including foreign body aspiration 7, 8
• Avoid relying solely on clinical assessment—clinical presentation alone is adequate in only 66% of cases 2

Management Principles

• Address the underlying pathologic process first before symptomatic treatment 1
• Optimize treatment of identified conditions (diuresis for renal failure, transfusion for severe anemia, thyroid replacement) 1
• Consider pulmonary rehabilitation for deconditioning regardless of underlying cause 1
• Refer to appropriate specialists based on identified etiology (nephrology for renal disease, hepatology for cirrhosis, neurology for neuromuscular disease) 1

Special Considerations

Thromboembolic disease (thrombophlebitis, pulmonary embolism) requires rest during acute phase, with gradual return to low-level activity once stable on anticoagulation 1

Myocarditis and endocarditis require activity restriction until inflammation resolves and infection is treated 1

Exercise-induced laryngeal dysfunction must be distinguished from true dyspnea through flexible laryngoscopy and appropriate exercise challenge 1